The long term goal of the proposed research is to provide a scientific basis for establishing clinical conditions for the safest use of shock wave lithotripsy (SWL), while preserving its high level of efficacy. Recent findings from our group show that a clinical level of SWL induces a vascular insult within the kidney characterized by hemorrhage, inflammation and reduced perfusion. While the efficacy of SWL is not in question, these findings raise concerns about the long-term safety of SWL. The first step in addressing these concerns requires an understanding of the injury caused by SWL. This proposal will employ cellular, structural, molecular and functional approaches to characterize this injury under a variety of treatment conditions. The research will be conducted in pigs to: 1) Define the relationship between the size of the SWL-induced lesion and impairment of renal hemodynamics; 2) Determine the progression of the acute inflammatory/fibrogenic response after SWL-induced injury (collaboration with Project 2); 3) Identify the cause of the SWL-induced renal vasoconstriction; 4) characterize possible risk factors for SWL; 5) Determine the roles of acoustic cavitation and shear forces in SWL-induced tubular and vascular injury (collaboration with Projects 4 and 5). The relationship between lesion size and impaired renal hemodynamics will be determined with whole-kidney clearance and quantitative morphological techniques. The role of potential mediators of SWL-induced vasoconstriction will be determined with specific antagonists for appropriate receptors. The time course for renal fibrogenesis induced by SWL will be determined with the aid of radio-labeled markers (platelets, red cells, leukocytes, microspheres, etc), and gene expression of selected and potential novel cytokines and vasoactive compounds (endothelin, nitric oxide, thromboxane, etc). Sensitive hydrophones will be used to correlate intrarenal sites of acoustic cavitation with regions of renal injury, and arrays of miniaturized pressure transducers, implanted on kidneys, will determine the relationship of shear forces to the injury. The formation gained from these studies may lead to improved patient selection criteria or therapeutic interventions to limit or prevent SWL-induced renal injury.